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  • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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  • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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  • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
  • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
  • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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  • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the present invention relates to lipid derivatives which may be used as PAF (Platelet Activating Factor) antagonist or antitumor agent in the field of medicine.
• PAF Platinum Activating Factor
• the invention relates to the compounds represented by the following formula (I).
• R 1 is alkyl or alkylcarbamoyl
• R 2 is lower alkoxy, lower alkylcarbamoyloxy, lower alkylcarbonylamino, lower alkyloxycarbonylamino, lower alkylureido, lower alkyloxymethyl, lower alkylcarbonylmethyl, cyanomethyl, heterocyclic group, or heterocyclyloxy
• R2 is hydrogen or taken together with R 2 forms -O(CH 2 ) m - wherein m is an integer of 1 to 5;
• R 3 , R 4 , and R 5 each is hydrogen or lower alkyl or two or three of R 3 , R 4 , and R 5 taken together with the adjacent nitrogen atom form cyclic ammonio;
• Rs is hydrogen or lower alkylcarbonyl;
• X- is a counter anion;
• Y is oxygen or sulfur; and
• n is an integer of 1 to 10.
• PAF which is represented by the following formula: wherein m indicates 16 or 18 is generated from basocyte, neutrophile, acidocyte, macrophage, mast cell, platelet, human leukemia cell, or vascular endothelial cell through various stimulations.
• PAF has been known to have the biological activities such as constriction of smooth muscle, decrease of coronary blood flow, inhibition of cardiac effect, increase of vascular permeability or hypotension. It is thought that PAF plays an important role in some physiological and pathological reaction, such as inflammation, asthma, thrombosis, anaphylactic shock, allergy, hypotension, ischemic heart disease, acute transplant rejection, nephritis, and gastric ulcer.
• PAF antagonists are being developed as agents for the treatment of those desease. [P.Braquet et al., Pharmacological Reviews, 39, 98-145, (1987)]. Some PAF antagonists which are structurally analogous to PAF are disclosed, for example, in JPN Kokai Nos. 57-67589, 60-243047, and 62-228088.
• Lipid derivatives represented by the formula: wherein R 1 is alkyl or alkylcarbamoyl; R 2 is lower alkyloxy, lower alkylcarbamoyloxy, lower alkylcarbonylamino, lower alkyloxycarbonylamino, lower alkylureido, lower alkyloxymethyl, lower alkylcarbonylmethyl, cyanomethyl, heterocyclic group, or heterocyclyloxy; R 2 ' is hydrogen or taken together with R 2 forms -O(CH 2 ) m - wherein m is an integer of 1 to 5; R 3 , R 4 , and R 5 each is hydrogen or lower alkyl or two or three of R 3 , R 4 , R 5 taken together with the adjacent nitrogen atom form cyclic ammonio; Rs is hydrogen or lower alkylcarbonyl; X- is a counter anion; Y is oxygen or sulfur; and n is an integer of 1 to 10.
• These compounds may be useful as PAF antagonists, e.g., as antithrombotic, antivasoconstricting, antibronchoconsticting agent or antitumor agent.
• PAF antagonists have been developed so far, they still have some problems; e.g., having no specific action to PAF receptor, possession of PAF-like action as well as PAF antagonistic effect, possession of side effect such as hemolysis, their metabolic unstability, and so on. These problems are desired to be solved.
• the inventors of the present invention have studied hard to develop useful PAF antagonists or antitumor agents. They found that PAF could be converted into PAF antagonists or antitumor agents if its phosphate moiety was substituted by sulfonamide. This invention is based on these findings.
• R 1 is alkyl or alkylcarbamoyl
• R 2 is lower alkyloxy, lower alkylcarbamoyloxy, lower alkylcarbonylamino, lower alkyloxycarbonylamino, lower alkylureido, lower alkyloxymethyl, lower alkylcarbonylmethyl, cyanomethyl, heterocyclic group, or heterocyclyloxy
• R2 is hydrogen or taken together with R 2 forms -O(CH 2 ) m - wherein m is an integer of 1 to 5;
• R 3 , R 4 , and R 5 each is hydrogen or lower alkyl or two or three of R 3 , R 4 , and R 5 taken together with the adjacent nitrogen atom form cyclic ammonio;
• R 6 is hydrogen or lower alkylcarbonyl;
• X- is a counter anion;
• Y is oxygen or sulfur; and
• n is an integer of 1 to 10.
• lower alkyl refers to straight or branched C 1 to C 7 alkyl, e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl.
• allyl refers to straight C 1 to C 35 alkyl which may have a double bond or triple bond.
• it refers to C 10 to C 30 higher alkyl, e.g., decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nanodecyl, icosyl, henicosyl, docosyl, tricosyl, tetracosyl, pentacosyl, hexacosyl, heptacosyl, octacosyl, nonacosyl, triacontyl.
• lower alkyl moiety corresponds to the above mentioned lower alkyl.
• heterocyclic group refers to 5- to 7-membered heterocyclic group, which may have one to four heteroatoms such as oxygen, sulfur, and/or nitrogen, optionally substituted by lower alkyl, lower alkyloxy, hydroxy, halogen, or lower alkyloxycarbonyl or the conbination. Those substituents on the heterocyclic group are sometimes referred to as "the substituent”.
• Heterocyclic group includes, for example, 1H-pyrrol-1-yl, 2-methyl-1 H-pyrrol-1-yl, 3-methyl-1 H-pyrrol-1-yl, 1H-imidazol-1-yl, 2-methyl-1 H-imidazol-1-yl, 2,4-dimethyl-1H-imidazol-1-yl, 1H-pyrazol-1-yl, 5-methyl-1H-pyrazol-1-yl, 3,5-dimethyl-1H-pyrazol-1-yl, 1H-1,2,3-triazol-1-yl, 4-methyl-1 H-1,2,3-triazoi-1-yl, 4-methyl-2H-1,2,3-triazol-2-yl, 4-methyl-3H-1,2,3-triazol-3-yl, 3-methyl-1H-1,2,4-triazol-1-yl, 3-methyl-2H-1,2,4-triazol-2-yl, 3-methyl-4H-1,2,4-triazol-4-yl, 2H-tetrazol-2
• heterocyclyloxy refers to hydroxy substituted by the heterocyclic group and includes, e.g., 3-isoxazolyloxy, 3-isothiazolyloxy, 3-pyrazolyloxy, 3-(4-methylisoxazolyl)oxy, 4-(1, 2,3-triazolyl)oxy, and 4-(5-methyl-1,2,3-triazolyl)oxy.
• cyclic ammonio refers to 5 or 6 membered mono-, bi-, or tricyclic ammonia which may contain heteroatoms and optionally be substituted by lower alkyl, carboxyl, lower alkyloxycarbonyl, hydroxy, lower alkyloxy, acyloxy, lower alkylamino, amino, carbamoyl,ureido or the like.
• Cyclic ammonio includes, e.g., N-methyl-1-pyrrolinio, N-methyl-1- pyrrolidinio, 3-oxazolio , 2-isoxazolio, 3-thiazolio, 4-methyl-3- thiazolio, 5-hydroxyethyl-4-methyl-3-thiazolio, 3-imidazolio, 1- pyridinio, 3-carboxy-1-pyridinio, N-methyl-1-piperidinio, N-methyl-4-morpholio, 1-pyrimidinio, 1-pyrazinio, N-methyi-1-piperazinio, 1-triazinio, 3-benzoxazolio, 3-benzothiazolio, 1-quinolinio, 6-methoxy-1-quinolinio, 5,6,7,8-tetrahydro-1-quinolinio, 2-isoquinolinio, 1-quinoxalinio, azirinio, or the like.
• counter anion refers to a pharmacologically acceptable anion such as halogen anion (e.g., chlorine, bromine, iodine), acetate anion, methylsulfonate anion, sulfate anion, nitrate anion, or phosphate anion.
• halogen anion e.g., chlorine, bromine, iodine
• acetate anion e.g., methylsulfonate anion, sulfate anion, nitrate anion, or phosphate anion.
• C 12 to C 20 higher alkyl e.g., dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, and icosyl
• alkyl e.g., dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, and icosyl
• C 16 to C 18 alkyl e.g., hexadecyl, heptadecyl, octadecyl, and the like are more desirable.
• R 1 is alkylcarbamoyl
• the alkyl moiety corresponds to the above mentioned alkyl, that is, dodecylcarbamoyl, tridecylcarbamoyl, tetradecylcarbamoyl, pentadecylcarbamoyl, hexadecylcarbamoyl, heptadecylcarbamoyl, octadecylcarbamoyl, nonadecylcarbamoyl, and icosylcarbamoyl are preferable examples for the alkylcarbamoyl and, especially, hexadecylcarbamoyl, heptadecylcarbamoyl, octadecylcarbamoyl, and the like are more desirable.
• lower alkyloxy for R 1 is methoxy, ethoxy, or propoxy
• lower alkylcarbamoyloxy for R 2 is methylcarbamoyloxy, ethylcarbamoyloxy, or propylcarbamoyloxy
• lower alkylcarbonylamino for R 2 is methylcarbonylamino, ethylcarbonylamino, or propylcarbonylamino
• lower alkyloxycarbonylamino for R 2 is methoxycarbonylamino, ethoxycarbonylamino, or propoxycarbonylamino
• lower alkylureido for R 2 is methylureido, ethylureido, or propylureido
• lower alkyloxymethyl for R 2 is methoxymethyl, ethoxymethyl, or propoxymethyl
• lower alkylcarbonylmethyl for R 2 is methylcarbonylmethyl, ethylcarbonylmethyl
• Especially preferable heterocyclic group for R 2 is N containing 5 or 6 membered heterocyclic group which may contain oxygen or sulfur and optionally have the substituent, e.g. 3-methyl-2H-1,2,4-triazol-2-yl, 3H-1,2,3,4-tetrazol-3-yl, 5H-1,2,3,4-tetrazol-5-yl, 5-methyl-1H-tetrazol-1-yl, 5-methyl-2H-tetrazol-2-yl.
• Heterocyclyoxy for R 2 refers to hydroxy substituted by the 5 or 6 membered heterocyclic which may contain one to four heteroatoms such as oxygen, sulfur, or nitrogen and optionally have the substituent, e.g., 3-isoxazolyloxy, or 3-(4-methylisoxazolyl)oxy.
• R 2 is methoxy, methylcarbamoyloxy, acetamido, methoxycarbonylamino, methylureido, methoxymethyl, acetylmethyl, cyanomethyl, 3-methyl-2H-1,2,4-triazol-2-yl, 5-methyl-1 H-tetrazol-1-yl, 5-methyl-2H-tetrazol-2-yl, or 3-isoxazolyloxy.
• R 2 and R 2 ' taken together may form -O(CH 2 )m-.
• m is an integer of 1 to 5, more desirably m is an integer, 4 or 5, and most desirably an integer, 4.
• Especially preferable lower alkyl for Rs, R 4 and R 5 lower alkyl is methyl, ethyl or propyl and the most desirable lower alkyl is methyl.
• cyclic ammonio is N-methyl-1-pyrrolinio, N-methyl-1-pyrrolidinio, 3-oxazolio, 2-isoxazolio, 3-thiazolio, 4-methyl-3-thiazolio, 5-hydroxyethyl-4-methyl-3-thiazolio, 1-N-methyl-3-imidazolio, 1-pyridinio.
• Especially preferable alkylcarbonyl for Rs is acetyl, propionyl, or butyryl and the most desirable R 6 is acetyl.
• n is an integer of 1 to 10, more desirably n is an integer, 1 to 5, and most desirably an integer, 2 to 4.
• the preferable lower alkyl for R 7 is above mentioned C 1 to C 7 alkyl, especially preferable lower alkyl for R 7 is methyl or ethyl, or propyl and most desirable lower alkyl for R 7 is methyl.
• Prot-OH refers to an ordinally used hydroxy protecting group such as benzyl, triarylmethyl, e.g., triphenylmethyl (trityl), trialkylsilyl, e.g., trimethylsilyl, tert-butyldimethylsilyl, tetrahydropyrany, acetyl, benzoyl, p-nitrobenzoyl, or the like.
• benzyl triarylmethyl, e.g., triphenylmethyl (trityl), trialkylsilyl, e.g., trimethylsilyl, tert-butyldimethylsilyl, tetrahydropyrany, acetyl, benzoyl, p-nitrobenzoyl, or the like.
• Prot-NH2 refers to an amino protecting group such as acetyl, benzoyl, benzoyloxycarbonyl, tert-butoxycarbonyl, trityl, or the like.
• the compound (I) contains two stereoisomers, i.e., those of R- and S-configuration.
• This invention includes each enantiomer, their mixture, and racemate thereof.
• the compound (I) of the present invention is prepared by the following process.
• This step can be carried out by hydrolysis of the N-substituted succinimide or N-substituted phthalimide derivative of the compound V.
• the reaction to prepare the N-substituted succinimide or N-substituted phthalimide derivatives of the compound V is carried out by reacting succinimide or phthalimide in the presence of triphenylphosphine and diethyl azodicarboxylate in a solvent such as tetrahydrofuran, benzene, or dimethylformamide (DMF) at room temperature for a period of several hours to several tens of hours.
• a solvent such as tetrahydrofuran, benzene, or dimethylformamide (DMF)
• the hydrolysis is carried out in the presence of hydrazine in a solvent such as alcohol (e.g., methanol, ethanol) at room temperature or under reflux condition for several hours.
• a solvent such as alcohol (e.g., methanol, ethanol) at room temperature or under reflux condition for several hours.
• the hydroxy of the compound V may be converted into the amino by allowing to react the methanesulfonyloxy or benzenesulfonyloxy derivatives of V with sodium azide or lithium azide, followed by the reduction of the azide-compound with a reducing agent such as triphenylphosphine.
• the compound IV is sulfonylated with a haloalkanesulfonyl halide represented by the formula Hal'-S0 2 (CH2)n-Hal wherein Hal and Hal' each is a halogen, and n is the same as defined above to give the sulfonamide derivative III.
• a haloalkanesulfonyl halide represented by the formula Hal'-S0 2 (CH2)n-Hal wherein Hal and Hal' each is a halogen, and n is the same as defined above to give the sulfonamide derivative III.
• the reaction is carried out in the presence of a base such as triethylamine, pyridine, sodium hydroxide in a solvent such as chlorinated hydrocarbon (e.g., chloroform, dichloromethane), ether (e.g., ethyl ether, tetrahydrofuran) or aromatic hydrocarbon (e.g., benzene) under cooling or at room temperature for a period of several hours to several tens of hours.
• a base such as triethylamine, pyridine, sodium hydroxide
• a solvent such as chlorinated hydrocarbon (e.g., chloroform, dichloromethane), ether (e.g., ethyl ether, tetrahydrofuran) or aromatic hydrocarbon (e.g., benzene)
• Dimethylaminopyridine may be added as a catalyst, if necessary.
• the compound prepared by this step is a chloride
• it can be further converted into other halides such as bromide or iodide by the treatment with sodium bromide or sodium iodide, respectively, in a usual manner.
• the compound previously prepared by this step may be allowed to react with an acylating reagent in the presence of a base such as triethylamine, pyridine, N,N-diisopropylethylamine in a chlorinated hydrocarbon, .e.g., dichloromethane, chloroform under cooling or at room temperature.
• a base such as triethylamine, pyridine, N,N-diisopropylethylamine in a chlorinated hydrocarbon, .e.g., dichloromethane, chloroform under cooling or at room temperature.
• the acylating reagent such as acid halide, e.g., acetyl chloride, propionyl chloride, butyryl chloride, isobutylryl chloride, valeryl chloride, isovaleryl chloride, pivaloyl chloride, pentanoyl chloride, hexanoyl chloride, heptanoyl chloride or acid anhydride.
• acid halide e.g., acetyl chloride, propionyl chloride, butyryl chloride, isobutylryl chloride, valeryl chloride, isovaleryl chloride, pivaloyl chloride, pentanoyl chloride, hexanoyl chloride, heptanoyl chloride or acid anhydride.
• acetic anhydride e.g., acetic anhydride, propionic anhdyride, butyric anhydride, isobutyric anhydride, valeric anhydride, isovaleric anhydride, pivalic anhydride, hentanoic anhydride, hexanoic anhydride, heptanoic anhydride is exemplified.
• the compound iii is converted into an ammonium compound to give the compound (I) of the present invention.
• alkylamine e.g., trimethylamine, triethylamine
• 5 to 6-membered mono-, bi-, or tricyclic amine which may contain heteroatom and/or have substituent (e.g., N-methylpyrrole, N-methylpyrrolidone, oxazole, isoxazole, thiazole, 4-methylthiazole, N-methylimidazole, pyridine, 3-carboxypyridine, N-methylpiperidine, N-methylmorpholine, pyrimidine, pyrazine, N-methylpiperazine, triazine, benzoxazole, benzothiazole, quinoline, isoquinoline, quinoxaline, azirine) is exemplified.
• substituent e.g., N-methylpyrrole, N-methylpyrrolidone, oxazole, isoxazole, thiazole, 4-methylthiazole, N-methylimidazole, pyridine, 3-carboxypyr
• the reaction is carried out using an amine itself as a solvent or in a solvent such as alcohol (e.g., methanol, ethanol), aromatic hydrocarbon (e.g., benzene, toluene), ether (e.g., ethyl ether, tetrahydrofuran, dioxane) or dimethylformamide at room temperature or under heating for a period of several hours to several tens of hours.
• alcohol e.g., methanol, ethanol
• aromatic hydrocarbon e.g., benzene, toluene
• ether e.g., ethyl ether, tetrahydrofuran, dioxane
• the chloride is substituted by bromide or iodide and the resulting compound is allowed to react with several kinds of amines to give an ammonium bromide or iodide which may be further treated with hydrochloric acid to give chloride.
• This step is carried out by oxidation of the phenylselenide compound or phenylthio compound, which can be prepared by substitution of the halogen of the compound III to phenylselenium anion or phenylthio anion, with a peroxide followed by heating the resulting compound to eliminate benzeneselenic acid or benzenesulfenic acid.
• the reaction to prepare the phenylselenyl compound or phenylthio compound is carried out using the reagents obtained by the reduction of diphenyldiselenide or diphenylsulfide with sodium borohydride in a solvent such as an alcohol (e.g., methanol, ethanol, isopropanol), an ether (e.g., ethyl ether, tetrahydrofuran) or dioxane at room temperature or under heating for several hours.
• a solvent such as an alcohol (e.g., methanol, ethanol, isopropanol), an ether (e.g., ethyl ether, tetrahydrofuran) or dioxane at room temperature or under heating for several hours.
• the oxidation is carried out using a peroxide such as an aqueous hydrogen peroxide, m-chloroperbenzoic acid, peracetic acid, tert-butyl hydroperoxide, or the like in a solvent such as an alcohol (e.g., methanol, ethanol) or a chlorinated hydrocarbon (e.g., dichloromethane, chloroform) at room temperature for several hours.
• a peroxide such as an aqueous hydrogen peroxide, m-chloroperbenzoic acid, peracetic acid, tert-butyl hydroperoxide, or the like in a solvent such as an alcohol (e.g., methanol, ethanol) or a chlorinated hydrocarbon (e.g., dichloromethane, chloroform) at room temperature for several hours.
• a peroxide such as an aqueous hydrogen peroxide, m-chloroperbenzoic acid, peracetic acid, tert-buty
• the reaction to eliminate the oxide by heating is carried out in a solvent such as an aromatic hydrocarbon (e.g., benzene, toluene) or a chlorinated hydrocarbon (e.g., dichloromethane, chloroform) under heating.
• a solvent such as an aromatic hydrocarbon (e.g., benzene, toluene) or a chlorinated hydrocarbon (e.g., dichloromethane, chloroform) under heating.
• the double bond of the compound VII is cleaved oxidatively to give the aldehyde which is then reduced to the compound Vl.
• the aldehyde is prepared by reductive decomposition of the ozonide which is obtained by the ozonization of the compound VII.
• the ozonization is carried out in a solvent such as a chlorinated hydrocarbon (e.g., dichloromethane, chloroform, carbon tetrachloride), an alcohol( e.g., methanol, ethanol), benzene, or ethyl acetate under cooling for several hours; if necessary, the solvent may be used in combination.
• a chlorinated hydrocarbon e.g., dichloromethane, chloroform, carbon tetrachloride
• an alcohol( e.g., methanol, ethanol), benzene, or ethyl acetate under cooling for several hours; if necessary, the solvent may be used in combination.
• the reductive decomposition of the ozonide is carried out using a reduced agent such as zinc dust in acetic acid, or triphenylphosphite trimethylphosphite, dimethylsulfide, sodium iodide, sulfur dioxide, sodium hydrogensulfite, tin(II) chloride, or iron(II) sulfate, or by catalytic reduction using a catalyst such as platinium, palladium, nickel, palladium on calcium carbonate.
• a reduced agent such as zinc dust in acetic acid, or triphenylphosphite trimethylphosphite, dimethylsulfide, sodium iodide, sulfur dioxide, sodium hydrogensulfite, tin(II) chloride, or iron(II) sulfate
• a catalyst such as platinium, palladium, nickel, palladium on calcium carbonate.
• the reduction converting the aldehyde to the alcohol is carried out using reducing agent such as metal hydride (e.g., lithium aluminum hydride, lithium borohydride, sodium borohydride, lithium trimethoxyaluminohydride, lithium tritert-butoxyaluminohydride) in a solvent such as an alcohol (e.g., methanol, ethanol) or ether (e.g., ethyl ether, tetrahydrofuran) at room temperature or under heating for several hours.
• metal hydride e.g., lithium aluminum hydride, lithium borohydride, sodium borohydride, lithium trimethoxyaluminohydride, lithium tritert-butoxyaluminohydride
• a solvent such as an alcohol (e.g., methanol, ethanol) or ether (e.g., ethyl ether, tetrahydrofuran) at room temperature or under heating for several hours.
• the halogenation is achieved by direct halogenation of the hydroxy using halogenating agent such as phosphorus halide (e.g., phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, phosphorus pentabromide) or thionyl halide (e.g., thionyl chloride, thionyl bromide) or indirect halogenation through an intermediate to which a leaving group is attached.
• halogenating agent such as phosphorus halide (e.g., phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, phosphorus pentabromide) or thionyl halide (e.g., thionyl chloride, thionyl bromide) or indirect halogenation through an intermediate to which a leaving group is attached.
• the reaction for introducing a leaving group is carried out with a compound forming the leaving group such as a substituted sulfonyl chloride (e.g., methanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride) in the presence of a base such as triethylamine, pyridine, or the like in the usual manner. Then, the resulting compound is allowed to react with an alkali metal halide such as lithium chloride, sodium bromide, or sodium iodide.
• a substituted sulfonyl chloride e.g., methanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride
• a base such as triethylamine, pyridine, or the like in the usual manner.
• an alkali metal halide such as lithium chloride
• the reaction is carried out, depending on the property of the halogenating agent, in a solvent such as a chlorinated hydrocarbon (e.g., dichloromethane, chloroform, carbon tetrachloride), a ketone (e.g. acetone, methyl ethyl ketone), or dimethylformamide in accordance with the usual manner.
• a chlorinated hydrocarbon e.g., dichloromethane, chloroform, carbon tetrachloride
• a ketone e.g. acetone, methyl ethyl ketone
• dimethylformamide e.g., dimethylformamide
• the halogen of the compound III' is substituted with an amide to give the compound (I) of the present invention.
• This step may be carried out in accordance with Step 3.
• anions of the compounds of the present invention which is prepared in Step 3 or this step may be exchange with other desired anions.
• the compound Va can be prepared by the following manner. wherein R 1 is alkylcarbamoylthio, Y is sulfur.
• the compound X6 is reductively cleaved to give the compound IX6 and the hydroxy of the compound IX6 is converted into the mercapto to give the compound VII6 which is then allowed to react with an isocyanate having the desired alkyl to give the compound VIA.
• the compound VA is prepared by removing the benzyl of the compound VIA.
• the reaction to prepare the compound IX6 from the compound X6 is carried out by using lithium aluminium hydride - aluminium chloride as a reducing agent.
• the step to prepare the compound VII6 from compound IX6 is achieved as follows.
• the hydroxy of the compound IX6 is converted into the leaving group by reaction with a compound which forms a leaving group, such as methanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, or the like in the presence of a base such as triethylamine according to the usual manner prior to the reaction with potassium thioacetate or sodium thioacetate to give the thioacetate VII6, which is then hydrolyzed with a base to give the mercapto derivative VII6.
• a compound which forms a leaving group such as methanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, or the like in the presence of a base such as triethylamine according to the usual manner prior to the reaction with potassium thioacetate or sodium thioacetate to give the thioacetate VII6, which is then
• the prepared compound VII6 is allowed to react with an isocyanate having a desired C 12 to C 2o alkyl such as dodecylisocyanate, hexadecylisocyanate, or octadecylisocyanate in a solvent such as pyridine to give the compound VIA.
• an isocyanate having a desired C 12 to C 2o alkyl such as dodecylisocyanate, hexadecylisocyanate, or octadecylisocyanate in a solvent such as pyridine to give the compound VIA.
• the compound VA is prepared by cleaving the benzyl ether of the compound VIA with trimethylsilyl iodide or aluminium chloridesodium iodide in acetonitrile under a neutral condition at temperatures of 0 °C to room temperature.
• the compound Vc can be prepared by the following manner. wherein R 7 is lower alkyl, Prot-OH is hydroxy protecting group, and R 1 , R 2 ', and Y each has the same meaning as defined before.
• an alcohol C1 is attached to an alkylisocyanate.
• alkylisocyanate methyl isocyanate, ethyl isocyanate, propyl isocyanate, isopropyl isocyanate, butyl isocyanate, tert-butyl isocyanate, or the like is exemplified.
• the reaction is carried out in a solvent such as chlorinated hydrocarbon e.g., dichloromethane, chloroform or dimethylformamide at room temperature or under heating for a period of several hours to several tens hours.
• a solvent such as chlorinated hydrocarbon e.g., dichloromethane, chloroform or dimethylformamide
• a catalyst such as an acid, e.g., boron trifluoride etherate, hydrochloric acid, aluminum chloride or a base, e.g, triethylamine, pyridine, 4-dimethylaminopyridine, 4-methylpiperidine may be used, if necessary.
• an acid e.g., boron trifluoride etherate, hydrochloric acid, aluminum chloride or a base, e.g, triethylamine, pyridine, 4-dimethylaminopyridine, 4-methylpiperidine
• a base e.g, triethylamine, pyridine, 4-dimethylaminopyridine, 4-methylpiperidine
• the deprotection is carried out in the presence of an acid, e.g., (1) trifluoroacetic acid, (2) acetic acid, (3) hydrogen bromide/acetic acid, (4) hydrochloric acid/chloroform.
• an acid e.g., (1) trifluoroacetic acid, (2) acetic acid, (3) hydrogen bromide/acetic acid, (4) hydrochloric acid/chloroform.
• the reaction may be carried out by catalytic hydrogenolysis in the presence of a palladium catalyst.
• the compound VE can be prepared by the following manner. wherein R 1 is alkylcarbamoyl, Y is oxygen, and Prot-N is amino protecting group, and R2', R 7 each has the same meaning as defined before.
• alkyl isocyanate used for this step dodecyl isocyanate, tridecyl isocyanate, tetradecyl isocyanate, pentadecyl isocyanate, hexadecyl isocyanate, heptadecyl isocyanate, octadecyl isocyanate, nonadecyl isocyanate, icosanyl isocyanate or the like is exemplified.
• the reaction is carried out in the same manner as described in Process (ii)-1.
• the deprotection of which condition depends on the protecting group, is carried out in the usual manner such as by catalytic hydrogenolysis (with palladium catalyst under atmospheric hydrogen at room temperature in methanol, methanol-acetic acid, or glacial acetic acid) or by mild acid treatment (aqueous acetic acid at 30 C or aqueous trifluoroacetic acid at -5 °C).
• the methoxycarbonyl of the compound E3 is reduced into the hydroxymethyl.
• a metal hydride complex e.g., lithium aluminumhydride, lithium borohydride, sodium borohydride, lithium trimethoxyaluminohydride, lithium tri-tert-butoxyaluminohydride, calcium borohydride resulted from calcium chloride and sodium borohydride is exemplified.
• the reaction is carried out in a solvent such as alcohol, e.g., methanol, propanol or ether, e.g., ethyl ether, tetrahydrofuran, glyme, diglyme under cooling for several hours.
• a solvent such as alcohol, e.g., methanol, propanol or ether, e.g., ethyl ether, tetrahydrofuran, glyme, diglyme under cooling for several hours.
• alkyl haloformate e.g., methyl chloroformate, methyl bromoformate, ethyl chloroformate, propylchloroformate, isopropyl chloroformate, butyl chloroformate, isobutyl bromoformate, tert-butyl chloroformate, pentyl chloroformate, hexyl chloroformate, heptyl chloroformate or dialkyl dicarbonate, e.g., dimethyl dicarbonate, diethyl dicarbonate, dipropyl dicarbonate, diisopropyl dicarbonate, dibutyl dicarbonate, di-tert-butyl dicarbonate, dipentyl dicarbonate, dihexyl dicarbonate, diheptyl dicarbonate is exemplified.
• alkyl haloformate e.g., methyl chloroformate, methyl bromoformate, ethyl chloroformat
• the reaction is carried out in a solvent such as ether, e.g., ethyl ether, tetrahydrofuran or ketone, e.g., acetone at room temperature for several hours.
• a solvent such as ether, e.g., ethyl ether, tetrahydrofuran or ketone, e.g., acetone at room temperature for several hours.
• the compound IV E2 can be prepared in the following manner. wherein R 1 is alkyl, Y is oxygen, and R 2 1 and R 7 each has the same meaning as defined before.
• This step can be carried out in the same procedure to prepared the compound VII6 from the compound IX6 in Process (i), that is, the alcohol e5 is converted into a sulfonate or halide which is then converted into the thioacetate with potassium thioacetate or sodium thioacetate.
• the thioacetate e6 is hydrolyzed with a base to give the thiol which is treated with sodium hydroxide to give the thiolate anion which is allowed to react with C 12 -C 20 alkyl halide, e.g., dodecyl bromide, tridecyl bromide, tetradecyl bromide, pentadecyl bromide, pentadecyl chloride, hexadecyl bromide, pentadecyl bromide, heptadecyl bromide, octadecyl bromide, octadecyl chloride, nonadecyl bromide, icosanyl bromide to give the compound E7.
• C 12 -C 20 alkyl halide e.g., dodecyl bromide, tridecyl bromide, tetradecyl bromide, penta
• This step can be carried out by using C 12 -C 20 alkylisocyanate in the same manner as described in Process (i).
• the reaction is carried out in the presence of an acid such as dilute hydrochloric acid or dilute sulfuric acid. 4
• an acid such as dilute hydrochloric acid or dilute sulfuric acid. 4
• the amino of the compound E8 is converted into the alkyloxycarbonylamino.
• This step can be carried out in the same manner as described in process (ii)-4.
• R 2 is alkylureido or alkanoylamino
• the compound IIIF or IIIG is prepared by the following manner. wherein R 1 , R 2 ', R 6 , R 7 , Y, and n each has the same meaning as defined before.
• This step is carried out in the usual manner for removing the urethane type amino protecting group, for example, hydrogen bromide or hydrochloric acid treatment in acetic acid, hydrochloric acid treatment in ethyl ether, ethyl acetate or nitromethane, or trifluoroacetic acid treatment.
• hydrogen bromide or hydrochloric acid treatment in acetic acid for example, hydrogen bromide or hydrochloric acid treatment in acetic acid, hydrochloric acid treatment in ethyl ether, ethyl acetate or nitromethane, or trifluoroacetic acid treatment.
• the compound IIIF is prepared by the addition of an alkylisocyanate to the amine IIIE'.
• the reaction is carried out using the C 1 -C 7 alkylisocyanate, e.g., methyl isocyanate, ethyl isocyanate, propyl isocyanate, isopropyl isocyanate, butyl isocyanate, tert-butyl isocyanate, pentyl isocyanate, hexyl isocyanate, heptyl isocyanate in an inactive solvent such as aromatic hydrocarbon, e.g., benzene, toluene, chlorobenzene, chlorinated hydrocarbon, e.g., chloroform, dichloromethane, ether, e.g., tetrahydrofuran, or acetone.
• aromatic hydrocarbon e.g., benzene, toluene, chlorobenzene, chlorinated hydrocarbon, e.g., chloroform, dichloromethane, ether, e.g., tetrahydro
• the acylating reagent such as acid halide, e.g., acetyl chloride, propionyl chloride, butyryl chloride, isobutylryl chloride, valeryl chloride, isovaleryl chloride, pivaloyl chloride, pentanoyl chloride, hexanoyl chloride, heptanoyl chloride or acid anhydride.
• acid halide e.g., acetyl chloride, propionyl chloride, butyryl chloride, isobutylryl chloride, valeryl chloride, isovaleryl chloride, pivaloyl chloride, pentanoyl chloride, hexanoyl chloride, heptanoyl chloride or acid anhydride.
• acetic anhydride e.g., acetic anhydride, propionic anhydride, butyric anhydride, isobutyric anhydride, valeric anhydride, isovaleric anhydride, pivalic anhydride, pentanoic anhydride, hexanoic anhydride, heptanoic anhydride is exemplified.
• reaction is carried out by heating without solvent or in an inactive solvent such as ethyl ether, benzene or the like.
• a base such as pyridine or an acid such as sulfuric acid may be added, if necessary.
• the compound VHIJ can be prepared by the following manner. wherein R 2 is heterocyclic group or heterocyclyloxy and R 1 , R21, Y and Prot-OH each has the same meaning as defined before.
• the protecting group selectively attached to the primary hydroxy such as tert-butyldimethylsilyl is used.
• the reaction is carried out using tert-butyldimethylchlorosilane in the presence of a base such as imidazole.
• the reaction is carried out using the desired heterocycle such as pyrrole, 2-methylpyrrole, 3-methylpyrrole, imidazole, 2-methylimidazole, 2,4-dimethylimidazole, pyrazole, 5-methyl pyrazole, 3,5-dimethylpyrazole, 1,2,3-triazole, 4-methyl-1,2,3-triazole, 3-methyl-1,2,4-triazole, 3,5- dimethyl-1, 2,4-triazole, tetrazole, or 5-methyltetrazole or 3-hydroxyisoxazole, 3-hydroxyisothiazole, 3-hydroxypyrazole, 3-hydroxy-4-methylisoxazole.
• the desired heterocycle such as pyrrole, 2-methylpyrrole, 3-methylpyrrole, imidazole, 2-methylimidazole, 2,4-dimethylimidazole, pyrazole, 5-methyl pyrazole, 3,5-dimethylpyrazole, 1,2,3-triazole, 4-methyl-1,2,3-triazole, 3-
• a dry ether solvent such as ethyl ether, tetrahydrofuran, or benzene.
• the deprotection is carried out in the usual manner such as the acetic acid treatment at room temperature or tetra-n-butylammonium fluoride treatment in tetrahydrofuran.
• This step can be carried out in the same manner as described in Processes (i), (ii)-1, or (iv)-1, 2.
• the deprotection is carried out in the usual manner using an agent such as acetic acid, hydrochloric acid/chloroform, hydrobromic acid/acetic acid, p-toluenesulfonic acid or the like.
• an agent such as acetic acid, hydrochloric acid/chloroform, hydrobromic acid/acetic acid, p-toluenesulfonic acid or the like.
• the compound IIIM can be prepared by the following manner. wherein R 1 , R 2 ', R 6 , R 7 , Y, n, Hal, and Prot-OH each has the same meaning as defined before.
• This step can be carried out in the same manner as described in Process II, Step 3'.
• This step can be carried out in the usual manner of Grignard reaction.
• aldehyde such as C 2 -C 8 aldehyde, e.g., acetoaldehyde, propionaldehyde, butyraldehyde, isobutyraldehyde, valeraldehyde, isovaleraldehyde, pivaloaldehyde, hexanol, heptanol, octanol is exemplified.
• the ordinally used hydroxy protecting group can be used.
• trialkylsilyl e.g., trimethylsilyl, tert-butyldimethylsilyl
• trialkylsilane such as trimethylchlorosilane or tert-butyldimethylchlorosilane is allowed to react in the presence of base such as imidazole.
• the compound M4 is cleaved to the compound M5.
• the reaction is carried out by treatment with an aqueous suspension of N-bromosuccinimide containing a trace of hydrobromic acid.
• This step is carried out in the same manner as described in Processes (i), (ii)-1, or (iv)-1, 2.
• the compound M6 is hydrolyzed with a base to give the compound M7.
• reaction is carried out in the usual manner with a base such as sodium hydroxide, potassium hydroxide, barium hydroxide, or the like in water or in alocohol (e.g., methanol, ethanol).
• a base such as sodium hydroxide, potassium hydroxide, barium hydroxide, or the like in water or in alocohol (e.g., methanol, ethanol).
• This step can be carried out in the same manner as described in Process I Step I.
• the compound M8 is sulfonylated to give the sulfonamide derivative M9.
• This step can be carried out in the same manner as described in process I Step 2.
• the deprotection is carried out as follows.
• protecting group is triarylmethyl, it is cleaved by treatment with acid
• protecting group is trialkylsilyl, it is cleaved by treatment with acetic acid or with tetra-n-butyl-ammonium fluoride in tetrahydrofuran
• protecting group is aroyl, it is cleaved by hydrolysis with a base such as sodium methoxide.
• chromate-type agent such as Jones' reagent, Collins' reagent, pyridinium chlorochromate or pyridinium dichromate, or dimethylsulfoxide combined with sulfur trioxide, trifluoroacetic anhydride, methanesulfonic anhydride, thionyl chloride or oxalyl chloride or the like may be used.
• a tertiary amine such as triethylamine or pyridine may be used as a decomposing agent.
• a chlorinated hydrocarbon such as chloroform or dichloromethane
• ether such as diethyl ether, tetrahydrofuran, or dimethylsulfoxide may be used.
• the reaction may be carried out under cooling or at room temperature within several hours.
• This step can be carried out in the same manner as described in Process (i), (ii)-1, or (iv)-1, 2.
• the step is carried out by using N-bromosuccinimide in a solvent such as chlorinated hydrocarbon (e.g., carbon tetrachloride, chloroform, dichloromethane ) by heating for several hours.
• a solvent such as chlorinated hydrocarbon (e.g., carbon tetrachloride, chloroform, dichloromethane ) by heating for several hours.
• This step can be carried out using metal cyanine such as sodium cyanide, potassium cyanide, copper(l) cyanide or the like in a solvent such as aeetone, acetonitrile, pyridine, ethyl ether, benzene, dimethylsulfoxide, dimethylformamide under heating.
• metal cyanine such as sodium cyanide, potassium cyanide, copper(l) cyanide or the like in a solvent such as aeetone, acetonitrile, pyridine, ethyl ether, benzene, dimethylsulfoxide, dimethylformamide under heating.
• a phase transfer catalyst such as crown ether, e.g., 18-crown-6 or tetraethylammonium cyanide may be used, if necessary.
• the benzoate N4 is hydrolysis to the alcohol.
• This step can be carried out in the same manner, the usual manner of the hydrolysis with a base, as described in Process (vii)-6.
• Example 4 the residue resulting from evaporating an amine is washed with n-hexane and in Examples 5 and 6, the said residue is washed with ethyl ether.
• the product is extracted with ethyl acetate, and the organic layer is washed with 1N-hydrochloric acid, saturated aqueous sodium hydrogencarbonate, and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and evaporated.
• the product is isolated by ethyl acetate extraction and the organic layer is washed with an aqueous sodium chloride, dried over anhydrous magunesium sulfate, and evaporated.
• To the residue are added 30 ml of benzene and 0.25 ml of pyridine and the mixture is heated at 45 °C to 50 °C for an hour. After the solvent is evaporated, the residue is purified by the column chromatography on silica gel with a n-hexane - ethyl acetate (2:1 to 1:1) mixture as an eluent.
• the product is isolated by ethyl acetate extraction and the organic layer is washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and evaporated.
• the residue is purified by the column chromatography on silica gel with a n-hexane - ethyl acetate mixture as an eluent to give 300 mg (0.59 mM) of 2-methoxy-1-octadecylcarbamoyloxy-3-(2-hydroxyethylsulfo- nylamino)propane Vla4 as a colorless powder in 50 % yield.
• reaction mixture is concentrated and the residue is purified by column chromatography on silica gel using a toluene - ethyl acetate (9:1 to 4:1) mixture as an eluent to give 17.027 g (33.6 mM) of the titled compound, 3-benzyloxy-2-methoxy-1-octadecylcarbamoylthiopropane VI6 as a solid in 98 % yield.
• the product is isolated by dichloromethane extraction and the dichloromethane layer is washed with an aqueous sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and evaporated.
• the residue is purified by the column chromatography on silica gel with a benzene - ethyl acetate (4:1) mixture as an eluent to give 83 mg (0.149 mM) of 3-(3-chloropropylsulfonylamino)-2-methoxy-1-octadecylcarbamoylthiopropane IIIa6 as a colorless powder in 67 % yield.
• the organic layer is subjected to Si0 2 (80 g) column chromatography and eluted with ethyl acetate:hexane (1:1) to afford crude crystals 2.07 g.
• the crystals are triturated and washed with pentane to yield the titled compound Vc1 1.205 g.
• the mother liqour is purified by Lobar column chromatography with the same solvent as described above to give additional Vc1 0.321 g (49% total yield), mp. 53-55°C.
• the crude phthalimide compound is recrystallizied from methanol-dichloromethane (10:1).
• a solution of 0.5 ml of trifluoroacetic acid in 2 ml of dichloromethane is added dropwise to a suspension of 252 mg of the BOC derivative III e2 in 5 ml dichloromethane at room temperature.
• the mixture is stirred at room temperature for 2 h and made alkaline with aqueous sodium hydrogencarbonate.
• the organic phase is separated and the aqueous phase is extracted with dichloromethane.
• the combined organic phases are washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
• the residue is purified by column silica gel chromatography using toluene:ethyl acetate (9:1 - -2:1) mixture as an eluent to obatin 1.84 g of crude 1-n-octadecylcarbamate derivative.
• a mixture of 1.84 g of the crude 1-n-octadecylcarbamate derivative obtained above and 150 mg (0.79mM) of p-toluenesulfonic acid monohydrate in 50 ml of methanol-tetrahydrofuran (1:1) mixture is stirred at room temperature for overnight.
• the prepared phthalimide is used for the next reaction without further purification.
• the dichloromethane layer is washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated.
• the residue is purified by column silfica gel chromatography using toluene-ethyl acetate (9:1) mixture and 0.81 g (99 % yield) of the titled compound II k1 is obtained.
• a suspension of 7.769 g (40 mM) of 5-hydroxymethyl-2-phenyl-1,3-dioxane n1 and 2.08 g (52 mM) of 60 % sodium hydride in oil in 150 ml of anhydrous benzene is heated at 50 ° C for 1 hour then a solution of 17.28 g (54 mM) of n-hexadecyl methanesulfonate in 50 ml of anhydrous benzene is added.
• the reaction mixture is heated under refluxing for 7 hours.
• the product is isolated by ethyl acetate extraction.
• the said starting material is prepared by the same procedure as described in (77), (79), (80), (81), (3), (4), and (5) using 3-methyl-2H-1,2,4-triazole instead of 5-methyltetrazole in (77).
• the said starting material is prepared by the same procedure as described in (77), (79), (80), (82), (3), (4), and (5) using 3-methyl-2H-1, 2, 4-triazole instead of 5-methyltetrazole in (77).
• the said starting material is prepared by the same procedure as described in (77), (79), (80), (82), (3), (4), and (5) using 3-methyl-2H-1, 2, 4-triazole instead of 3-methyltetrazole in (77).
• the compounds of the present invention are the PAF analogues which act as PAF receptor antagonist and/or antitumor agent.
• the compounds of the present invention inhibit the platelet from aggregation induced by PAF and may be useful agents for the treatment of physiological and pathological disorders in which PAF may participate, for example, endotoxic shock, asthma, inflammation, acute tissuetransplant rejection, hypotension, gastric ulcer, and nephritis.
• endotoxic shock for example, endotoxic shock, asthma, inflammation, acute tissuetransplant rejection, hypotension, gastric ulcer, and nephritis.
• the platelet aggregation inhibitory activities ( in vitro ) of the representative compounds of the present invention are shown below.
• the blood sample in each tube was gently shaken and then centrifuged for 10 minutes at 200 g at 22 °C to give platelet rich plasma (PRP).
• the remaining blood was further centrifuged at 3,000 rpm (about 1,900 g) for 10 minutes at 22 °C to give platelet-poor plasma (PPP).
• PRP was diluted with PPP to prepare a blood sample whose platelet number was 50 - 55 x 10 4 / ⁇ l. The sample was then subjected to a platelet aggregation test.
• the platelet aggregation was examined by the method of Born [Born G.V.R., Nature, 194, 927-929 (1962)], using a Type AUTO RAM-61 aggregometer, (Rika Denki Co., Ltd., Tokyo).
• PRP was warmed at 37 ° C for 1 minute with stirring at 1,200 rpm, and then a solution of the test compound [dimethylsulfoxide solution (1 ⁇ l) of the compound + saline (9 ⁇ l)] was added thereto.

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• 1988
  • 1988-11-29 US US07/284,590 patent/US5047540A/en not_active Expired - Fee Related
  • 1988-12-16 DE DE8888311975T patent/DE3875927T2/de not_active Expired - Fee Related
  • 1988-12-16 AT AT88311975T patent/ATE82272T1/de active
  • 1988-12-16 ES ES88311975T patent/ES2045152T3/es not_active Expired - Lifetime
  • 1988-12-16 EP EP88311975A patent/EP0321296B1/de not_active Expired - Lifetime
  • 1988-12-17 KR KR88016880A patent/KR960009428B1/ko not_active Expired - Lifetime
• 1992
  • 1992-12-21 GR GR920403030T patent/GR3006619T3/el unknown

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